Studies in this laboratory have developed the following hypothesis for the pathogenesis of the neurotoxicology of hexane, an environmental toxin of petroleum origin and a hazard of occupational exposure and inhalant drug abuse, viz., hexane is metabolized by the liver to the gamma-diketone, 2,5-hexanedione, which reacts with amino groups of proteins resulting in cross-linking through the formation of a stable, conjugated imine; progressive cross-linking of neurofilaments during slow axonal transport generates aggregates too large to pass through nodes of Ranvier; the ensuing obstruction of slow axonal transport results in degeneration of the distal axon. This hypothesis is based on our observations that in the reaction of 2,5-hexanedione with primary amines, poly-L-lysine, and proteins an orange chromophore develops with the absorption (lambda max equals 470nm) and fluorescent (Ex lambda equals 370nm, Em lambda equals 435 and 545 nm) properties of a conjugated imine, as had been previously described in the reaction between amines and malonaldehyde. The development of this chromophore with proteins results in a proportional loss of lysinyl residues by trinitrobenzene sulfonate titration and is attended by progressive intramolecular and intermolecular protein cross-linking. To test this hypothesis we shall (1) administer monoketones to rats to determine the relationships between diketone synthesis, diketone structure, clinical neurotoxicology, paranodal neurofilament accumulation and axonal degeneration; (2) characterize the kinetics of reaction of gamma-diketones with primary amines and with lysinyl groups of neurofilaments and other proteins; (3) establish proof of structure of the conjugated imine through model compound synthesis, (4) define whether reaction with neurofilaments results in aggregation through covalent cross-linking or via hydrophobic interactions; (5) seek morphologic, autoradiographic, and gel electrophoretic evidence for progressive neurofilamant cross-linking by gamma-diketones during slow axonal transport and obstruction of transport at nodes of Ranvier; and (6) determine whether additional environmental toxins which result in neurofilament accumulation do so via covalent cross-linking. Understanding the mechanism of neurofilament accumulation in hexane toxicity will direct prevention and therapy and allow generalizations to be made to oth (Text Truncated -Exceeds Capacity)